端木·宇 2008-6-19 22:18
Mutations
Mutations are errors in the genotype that create new alleles and canresult in a variety of genetic disorders. In order for a mutation to beinherited from one generation to another, it must occur in sex cells,such as eggs and sperm, rather than in somatic cells. The best way todetect whether a genetic disorder exists is to use a [b]karyotype[/b], a photograph of the chromosomes from an individual cell, usually lined up in homologous pairs, according to size.
[b] Autosomal Mutations[/b]
Some human genetic illnesses are inheritedin a Mendelian fashion. The disease phenotype will have either aclearly dominant or clearly recessive pattern of inheritance, similarto the traits in Mendel’s peas. Such a pattern will usually only occurif the disease is caused by an abnormality in a single gene. Themutations that cause these diseases occur in genes on the [b]autosomal chromosomes[/b],as opposed to sex-linked diseases, which we cover later in thischapter. (Be careful not to confuse autosomal chromosomes with somaticcells; autosomal chromosomes are the chromosomes that determine bodilycharacteristics and exist in [i]all[/i] cells, both sex and somatic.)
[b] Recessive Disorders[/b]
A Mendelian genetic illness initiallyarises as a new mutation that changes a single gene so that it nolonger produces a protein that functions normally. Some mutations,however, result in an allele that produces a nonfunctional protein. Adisease resulting from this sort of mutation will be inherited in arecessive fashion: the disease phenotype will only appear when bothcopies of the gene carry the mutation, resulting in a total absence ofthe necessary protein. If only one copy of the mutated allele ispresent, the individual is a heterozygous carrier, showing no signs ofthe disease but able to transmit the disease gene to the nextgeneration. Albinism is an example of a recessive illness, resultingfrom a mutation in a gene that normally encodes a protein needed forpigment production in the skin and eyes. The [b]pedigree [/b]shown below diagrams three generations of a hypothetical family affected by albinism.
[align=center][img]http://www.24en.com/d/file/sat/sat2/biology/2008-01-24/aa9e6f40f84e5957a251371df80f64eb.gif[/img][/align] The pedigree demonstrates the characteristicfeatures of autosomal recessive inheritance. The parents of an affectedindividual usually show no signs of disease, but both must at least beheterozygous carriers of the disease gene. Among the offspring of twocarriers, 25 percent will have the disease, 50 percent will becarriers, and 25 percent will be noncarriers. No offspring produced bya carrier and a noncarrier will have the disease, but 50 percent willbe carriers. Although not shown in this pedigree, offspring produced bytwo individuals who have the disease in their phenotype, which meansboth parents are recessive homozygous, will all develop the disease.
Many recessive illnesses occur with muchgreater frequency in particular racial or ethnic groups that have ahistory of intermarrying within their own community. For example,Tay-Sachs disease is especially common among people of Eastern EuropeanJewish descent. Other well-known autosomal recessive disorders includesickle-cell anemia and cystic fibrosis.
[b] Dominant Disorders[/b]
Usually, a dominant phenotype results fromthe presence of at least one normal allele producing a protein thatfunctions normally. In the case of a dominant genetic -illness, thereis a mutation that results in the production of a protein with anabnormal and harmful action. Only one copy of such an allele is neededto produce disease, because the presence of the normal allele andprotein cannot prevent the harmful action of the mutant protein. If arecessive mutation is like a car with an engine that cannot start, adominant mutation is like a car with an engine that explodes. A sparecar will solve the problem in the first case, but will do nothing toprotect the garage in the second case.
Huntington’s disease, which killedfolksinger Woody Guthrie, is a dominant genetic illness. A singlemutant allele produces an abnormal version of the Huntington protein;this abnormal protein accumulates in particular regions of the brainand gradually kills the brain cells. By middle age, this progressivebrain damage produces severely disturbed physical movements, loss ofintellectual functions, and personality changes. The pedigree shownbelow diagrams three generations of a hypothetical family withHuntington’s disease.
[align=center][img]http://www.24en.com/d/file/sat/sat2/biology/2008-01-24/bf276cacd6d549baea0bd9297031e2b3.gif[/img][/align] This pedigree demonstrates thecharacteristic features of autosomal dominant inheritance. Notice thatall affected individuals have at least one parent with the disease.Unlike recessive inheritance, there is no such thing as a carrier: thedisease will affect [i]all [/i]heterozygous individuals. Among theoffspring of an affected heterozygote and an unaffected person, 50percent will be affected and 50 percent will be unaffected. None of thechildren born to two unaffected individuals will have the disease.(Although not shown in this pedigree, homozygous dominant mutationsoften produce very severe cases of the disease, because the amount ofthe abnormal protein is doubled and the normal protein is entirelyabsent.)
[b] Chromosomal Disorders[/b]
Recessive and dominant characteristicsresult from the mutation of a single gene. Some genetic disordersresult from the gain or loss of an entire chromosome. Normally, pairedhomologous chromosomes separate from each other during the firstdivision of meiosis. If one pair fails to separate, an event called [b]nondisjunction[/b],then one daughter cell will receive both chromosomes and the otherdaughter cell will receive none. When one of these gametes joins with anormal gamete from the other parent, the resulting offspring will haveeither one or three copies of the affected chromosome, rather than theusual two.
[i] Trisomy[/i]
A single chromosome contains hundreds tothousands of genes. A zygote with three copies of a chromosome(trisomy), instead of the usual two, generally cannot survive embryonicdevelopment. Chromosome 21 is a major exception to this rule;individuals with three copies of this small chromosome (trisomy 21)develop the genetic disorder called Down syndrome. People with Downsyndrome show at least mild mental disabilities and have unusualphysical features including a flat face, large tongue, and distinctivecreases on their palms. They are also at a much greater risk forvarious health problems such as heart defects and early Alzheimer’sdisease.
[i] Monosomy[/i]
The absence of one copy of a chromosome (monosomy)causeseven more problems than the presence of an extra copy. Only monosomy ofthe X chromosome (discussed below) is compatible with life.
[i] Polyploidy[/i]
Polyploidy occurs when a failure occursduring the formation of the gametes during meiosis. The gametesproduced in this instance are diploid rather than haploid. Iffertilization occurs with these gametes, the offspring receive anentire extra set of chromosomes. In humans, polyploidy is always fatal,though in many plants and fish it is not.
[b] Sex Chromosomes and Sex-Linked Traits[/b]
Dominant and recessive illnesses occur withequal frequency in males and females. This is because the genesinvolved are located on autosomes, which are the same in both genders.Many physical traits, however, obviously do differ between the twogenders. In addition, gender dramatically affects the inheritance ofcertain traits and illnesses that have no obvious connection to sexualcharacteristics.
These sex-linked traits are controlled bygenes located on the sex chromosomes. Humans have 46 chromosomes,including 44 autosomes (nonsex chromosomes) and the two sexchromosomes, which can be either X or Y. The autosomes come in 22homologous pairs, present in both males and females. Females alsopossess a homologous pair of X chromosomes, while males have one Xchromosome and one Y chromosome (the master gene for “maleness” islocated on the Y chromosome). All eggs have an X chromosome, so the sexof a child is determined at the time of fertilization by the type ofsperm. If the fertilizing sperm carries an X chromosome, the child willbe female; if it carries a Y chromosome, the child will be male. The Xchromosome is much larger than the tiny Y chromosome, and most of thegenes on the X chromosome do not have a homologous counterpart on theY.
Genes on autosomes will always be present intwo copies: one inherited from the maternal parent, the other from thepaternal parent. The traits controlled by such autosomal genes will begenerally unaffected by gender and will follow Mendelian patterns ofinheritance (with the exceptions noted in previous sections). Incontrast, genes on the X chromosome (X-linked genes) are present in twocopies in females but only one copy in males. Female offspring willinherit one copy of an X-linked gene from each parent, but maleoffspring must inherit the Y chromosome from their father and thereforealways inherit only the maternal allele of any X-linked gene. Forexample, color blindness and hemophilia are sex-linked disorders. Themutated gene that causes these disorders is recessive and exists on theX chromosome. In order for a female, who is XX, to have a phenotypethat is color blind or hemophiliac, both of her parents have to havethe recessive gene. But since males have only one X chromosomeinherited from their mother, if their mother expresses the recessivemutation, that trait will [i]automatically [/i]be expressed in the male child’s phenotype, since the male has no other gene to assert dominance over the recessive mutation.
The pedigree shown below diagrams three generations of a hypothetical family affected by hemophilia A.
[align=center][img]http://www.24en.com/d/file/sat/sat2/biology/2008-01-24/b2352968733133e1c2dc9d21e9f5e039.gif[/img][/align] This pedigree demonstrates many of thecharacteristic features of X-linked recessive inheritance. Heterozygousfemales are carriers who do not express the disease. In contrast, allmales with the mutated allele will express the disease; there are nomale carriers. Affected males will transmit the mutated allele to noneof their sons but to all of their daughters, who will then all becarriers. Heterozygous females will transmit the disease to one-half oftheir sons, and one-half of their daughters will be carriers. Affectedmales generally have an unaffected father and a mother who is acarrier; 50 percent of their maternal uncles will have the disease.
